This proposal will test the idea that the "receptor presentation" avenue of T cell help to B cells is averted by T cell tolerance and B cell death under physiological circumstances. Development of functional memory B cells, with hallmarks of affinity maturation and somatic hypermutation, requires cognate and MHC-restricted T cell help. This help is often rationalized as a checkpoint that evolved to preclude autoreactive B cells from progressing on their own. However, in addition to presenting foreign antigen-derived peptides in class II MHC, the activated B cell also self-presents peptides from its receptor (BCR) variable (V) region, and these peptides can be immunogenic with respect to CD4 v helper T cells. This opens a potentially dangerous avenue of T cell help to B cells. Accordingly, we propose that this "receptor presentation" avenue of T cell help to B cells is normally precluded in the physiological state. During the past 3 years, we developed a unique model and reagents to test this hypothesis and obtained novel results indicating a role for both T cell tolerance and B cell inhibition in precluding antibody responses via receptor presentation. Now we propose to define the T cell tolerance and B cell inhibition mechanisms and to advance resolution of the model. Our studies will include T cell reactions to germline-encoded Ig V regions produced by preimmune B cells (Aim 1). They will also encompass interactions between T cells and B cells during the germinal center reaction, when somatic hypermutation of BCR genes and memory B cell development normally take place (Aims 2-3). The results obtained from this work will significantly advance our comprehension of important regulatory events that confer humoral immunity without autoimmunity. They will lead to improvements in the design of therapeutic mAb and passive transfer strategies that avert an unwanted immune reaction by the host against the mAb. Finally, they will provide useful information for the design of clone-specific vaccines to elicit T cell reactions to tumors of the B cell lineage.